Despite extensive diabetes research, the prevention and control of type 2 diabetes mellitus (type 2 DM) remain unclear. Diet has been shown to play a definite role in the onset of type 2 DM, and the diets commonly consumed in the United States and other westernized countries appear to increase the incidence of diabetes (J. S. Carter et al., Ann. Int. Med., 125, 221 (1996)). The high refined sugar and high fat content of U.S. diets are likely to be partly responsible, but the low intake of traditional herbs, spices, and other plant products may also be involved. The recommended use of plants in the treatment of diabetes dates back to approximately 1550 BCE (A. M. Gray et al., Br. J. Nutr., 78, 325 (1997)). For the majority of the world population, drug treatment for diabetes is not feasible and alternative treatments need to be evaluated.
Plants are important not only for the control of type 2 DM but also for its prevention, especially for people with elevated levels of blood glucose and glucose intolerance who have a greater risk of developing diabetes. Common spices such as cinnamon, cloves, and bay leaves display insulin potentiating activity in vitro (A. Khan et al., Biol. Trace Elem. Res., 24, 183 (1990)). It was thought that these spices might also have high chromium (Cr) concentrations, because biologically active forms of Cr potentiate insulin activity. However, there are no correlations between total Cr concentrations and insulin potentiating activity in these plant products (See, A. Khan et al., cited above). Only a small portion of the total Cr in biological systems is associated with insulin potentiating activity.
From an aqueous extract of commercial cinnamon, R. A. Anderson et al., J. Agric. Food Chem., 52, 65 (2004) have identified polyphenolic polymers that increase glucose metabolism roughly 20-fold in vitro in the epididymal fat cell assay. These appear to be rather unique, because other cinnamon or similar compounds display little or no biological activity. Additionally, approximately 50 plant extracts have also been investigated in this assay, and none have shown activity equal to that of cinnamon (C. L. Broadhurst et al., J. Agric. Food Chem., 48, 849 (2000)).
Recently, R. A. Anderson et al., (cited above) extracted cinnamon samples with acetic acid and ethanol and isolated fractions with insulin-enhancing activity using HPLC. Spectral analysis indicated the presence of, inter alia, doubly-linked aromatic polyphenols. The structures are shown below (Formula I).

The fractions containing these polyphenols, or A-type proanthocyanidins, were shown to have insulin-enhancing biological activity in an in vitro assay measuring the insulin-dependent effects on glucose metabolism. See, R. A. Anderson et al., J. Agric. Food Chem., 26, 1219 (1978). The fractions also were active as antioxidants. N. W. Schoene et al., Nutr. Res., 20, 47 (2000). These same compounds have been shown to inhibit phosphotyrosine phosphatases in the insulin-receptor domain and to activate insulin receptor kinase, and to function as a mimetic for insulin in 3T3-L1 adipocytes. J. Imparl-Radosevich et al., Hormone Res., 50, 177 (1998); J. Am. Coll. Nutr., 20, 327 (2001). Water-soluble polymeric polyphenols from cinnamon have also been shown to inhibit proliferation and to alter cell cycle distribution patterns of hematologic tumor cell lines. N. W. Schoene et al., Cancer Lett., 230, 134 (2005).
However, compounds of Formula I are difficult to synthesize, as are intermediates useful in such syntheses. S. Morimoto et al., Chem. Pharm. Bull., 35, 4717 (1987) prepared proanthocyanins A-G (III) and A-7 (IV) in low yield by the oxidation of procyanidin B-5 (II) with hydrogen peroxide in the presence of sodium bicarbonate. See FIG. 1. A. Pomilo et al., Liebigs. Ann. Chem., 597 (1977) reacted flavylium perchloride (V) with (+) catechin in aqueous methanol to yield compound VII in 2-3% yield. (See FIG. 2). Therefore, there is a continuing need for methods to prepare bioactive polyphenols, such as those derived from cinnamon.